Adverse weight gain is a consistently documented side effect associated with many different types of drug therapies. It is not known precisely how many of these drugs there are. A good list provided by Dr. George L. Blackburn, an obesity authority at Harvard University, includes more than 50 common drugs for the treatment of a range of disorders and conditions. (see, Blackburn, G L. Weight gain and antipsychotic medication. J. Clin. Psychiatry 2000; 61(8S): 36-42). The major therapeutic areas with currently known drugs associated with adverse weight gain include, but are not limited to: anti-diabetics, anti-depressants, anti-psychotics, anti-convulsants, anti-epileptics, oral contraceptives, cancer therapy, preventative migraine therapy, therapy for systemic inflammatory conditions, endometriosis therapy, osteoporosis therapy, hair growth therapy, and HIV therapy. Drug-induced adverse weight gain can be severe or mild depending on the treatment. The adverse weight gain can lead to overweight, and obesity (i.e. BMI>30 kg/m2), and may exacerbate many health problems, both independently and in associations with other diseases, and clearly associated with increased morbidity and mortality.
Adverse weight gain ranks among the main reasons these patient populations stop taking some medications (i.e. poor compliance) or contributes to their reluctance to start such treatment in the first place. This side effect presents a serious problem for those who urgently need to treat health problems that are often times far more dangerous than weight gain. Switching to another drug with a lower risk of adverse weight gain is an alternative approach, although this carries a risk of loss of clinical effectiveness. In some cases, the drugs that will most benefit the subject also have the highest incidence of side effects, particularly undesirable side effects such as adverse weight gain. Often times, however, no other appropriate treatments are available.
Therefore, there is a continuing need for new methods of treating adverse weight gain associated with drug therapies. Nowhere is this need more urgently felt than with people who suffer from diabetes mellitus (‘diabetes’). The majority of people who develop diabetes, especially types 2 diabetes, either are or have been obese. That means any additional weight gain would exacerbate their diabetes and contribute to the development or progression of obesity-related complications such as hypertension, dyslipidemia, coronary heart disease, stroke, gallbladder disease, osteoarthritis, sleep apnea, and respiratory problems, metabolic syndrome, and endometrial, breast, prostate, and colon cancers, just to name a few.
Diabetes affects an estimated 16 million people in the United States, 90% of whom suffer from type 2 diabetes, formerly referred to as Non-insulin Dependent Diabetes Mellitus, which is a serious, life-threatening disease. (see, Malinowski, J, Rosiglitazone in the Treatment of Type 2 Diabetes Mellitus: A Critical Review, Clin. Therap. 22, 10:1151-1168 (2000)). Type 2 diabetes is the fourth leading cause of death in the United States and a major contributor to blindness, chronic renal failure, and foot and leg amputations in adults. (see, U.S. Department of Health and Human Services. Diabetes Statistics, Bethesda, Md., National Diabetes Information Clearinghouse, October 1995, NIH Publication, 96-236.) Sufferers of type 2 diabetes, presents as a spectrum of metabolic abnormalities relative insulin deficiency and prominent inability to utilize the insulin that is produced by their bodies (i.e. insulin resistance).
The current approach to management of drug therapy in patients with type 2 diabetes is to start with oral drugs. In the United States, there are five classes of drugs that are approved for the treatment of type 2 diabetes and are set out in Table 1.
TABLE 1Different classes of anti-diabetic drugsDrugSide EffectsSulfonylureas, including firstSulfonylurea therapy is usuallygeneration (e.g., tolbutamide) andassociated with weight gain duesecond generation (e.g., glyburide)to hyperinsulinemia.sulfonylureas.Biguanides - metformin (e.g.Metformin reduces plasma glucoseGlucovance ®)via inhibition of hepatic glucoseproduction and increase of muscleglucose uptake. It also reducesplasma triglyceride and LDL-cholesterol levels.Alpha-glucosidase inhibitors -The major side effects are gas,acarbose (e.g. Precose ®)bloating, and diarrhea.Thiazolidinediones troglitazone (e.g.The major side effects are weightResulin ®), rosiglitazone (e.g.gain and an increase in LDL-Avandia ®) and pioglitazone ®.cholesterol levels.Meglitinides - Repaglinide (e.g.Weight gain, gastrointestinalPrandin ®)disturbances, and hypoglycemiaare common side effects.
Patients with type 2 diabetes often become less responsive to a single class of drugs over time, so that combination therapy of two or more of the classes of drugs is often needed for adequate control of blood glucose levels. Many of these anti-diabetic drugs cause adverse weight gain, as indicated above. That means many drug therapy for diabetes would likely involve one or more of the classes of drugs associated with adverse weight gain. Further, insulin is usually added when glycemic control is suboptimal at maximal doses of the oral drug. Weight gain is a well-documented common side effect of insulin. (see, Sinha A, et al., Effect of insulin on body composition in patients with insulin-dependent and non-insulin-dependent diabetes. Diabetes Med 1996; 13:40-46.)
Weight loss drugs for the treatment of obesity include orlisat (Davidson, M. H. et al. (1999) JAMA 281:235-42), dexfenfluramine (Guy Grand, B. et al. (1989) Lancet 2:1142-5), sibutramine (Bray, G. A. et al. (1999) Obes. Res. &:189-98) and phentermine (Douglas, A. et al. (1983) Int. J. Obes. 7:591-5). However, the side effects of these drugs and anti-obesity agents may limit their use. Dexfenfluramine was withdrawn from the market because of suspected heart valvulopathy; orlistat is limited by gastrointestinal side effects; and the use of sibutramine is limited by its cardiovascular side effects which have led to reports of deaths and its withdrawal from the market in Italy.
Recently, it has been suggested in PCT published patent application WO 04/018041 that a combination therapy of fibrate, an activator of peroxisome proliferators activated receptor alpha agonists (“PPAR-α”), and the Thiazolidinediones class of drugs, specifically rosiglitazone, would off-set some of the adverse weight gain associated with the treatment of the drugs alone or in combination therapy with other anti-diabetic therapies. The combination therapy of fibrate and rosiglitazone is not useful if the patient is taking cholesterol-lowering statins such as Lipitor™, Zocor™, and Crestor™. Combined statin-fibrate therapy appears to increase the risk of rhabdomyolysis and severe myopathy and should only be undertaken with extreme caution (see, Shek, A. et al, Statin-fibrate combination therapy; The Annals of Pharmacotherapy: Vol. 35, No. 7, pp. 908-917 (2001)). PCT published patent application WO 04/110375 discloses another combination therapy for treating obesity by administering to a subject in need thereof a composition comprising an anti-obesity agent and an anti-diabetic agent.
Being that adverse weight gain is one of the top contributors to discontinuing medications, it is a side effect that must be dealt with effectively. The absence of a method to treat the adverse weight gain continues to be a major medical challenge, particularly for people with diabetes. Thus, there clearly remains an unmet medical need for treatments of diseases, with therapeutics that do not have the side effect of adverse weight gain.
The present invention addresses this problem by providing a new method for treating the adverse weight gain associated with drug therapies, particularly drug therapies for diabetes, comprising administering to a subject in need thereof a therapeutically effective amount of an SCD-1 inhibitor, in conjunction with a pharmaceutically acceptable diluent or carrier. Subjects with drug-induced adverse weight gain treated with an SCD-1 inhibitor are expected to gain less weight than those treated with the drug alone. As a result, the combination therapy is more likely to result in the subjects continuing with the treatment and ameliorate other medical complications often associated with such adverse weight gain. Further, it is an object of this invention to provide a pharmaceutical composition for use in treating the adverse weight gain associated with drug therapies.